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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.
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PMID:Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline. 209 26

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.
Hypertension 1990 Jun
PMID:ES-8891, an orally active inhibitor of human renin. 211 12

The novel compound BW A575C, N-(1-(S)-carboxy-5-[4-(3-isopropylamino-2-(R,S)-hydroxypropoxy)-indole-2 - carboxamido]pentyl)-(R,S)-alanyl-(S)-proline, is a potent angiotensin converting enzyme (ACE) inhibitor and beta-blocker in vitro. It was therefore of considerable interest to establish whether this novel pharmacological profile was maintained in vivo. In conscious instrumented normotensive rats and dogs, intravenous and oral administration of BW A575C causes a dose-dependent rightward displacement of the pressor dose-response curve to angiotensin I (dose ratio of 29.5 and 16.1 in rats and dogs, respectively, at 1.0 mg/kg i.v.) and the tachycardia dose-response curve to isoprenaline (dose ratio of 3.1 and 8.0 in rats and dogs, respectively, at 1.0 mg/kg i.v.). In these experiments BW A575C is approximately 2-10 times more active as an ACE inhibitor than as a beta-blocker. In conscious instrumented acute renovascular hypertensive dogs, where plasma renin activity is elevated 10-fold, BW A575C (1.0 mg/kg i.v.) causes a reduction in blood pressure of 35% within 10 min of injection, which is sustained for up to 4 h. This reduction in blood pressure is accompanied by a consistent, but nonsignificant, reduction in heart rate. These results confirm the novel pharmacological profile of BW A575C in vivo and demonstrate that this compound is an effective antihypertensive agent in a renin-dependent model of hypertension.
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PMID:BW A575C: pharmacological profile in vivo of a novel angiotensin converting enzyme inhibitor and beta-blocker. 245 71

To assess metabolic functions of the pulmonary circulation during lung injury and subsequent recovery from injury, we measured angiotensin-converting enzyme (ACE) activity by means of benzoyl-phenylalanyl-alanyl-proline (BPAP) hydrolysis and 5-hydroxytryptamine (5-HT) removal in vivo in three groups of anesthetized rabbits. One group was treated with 30 micrograms/kg/day phorbol myristate acetate (PMA) intravenously 10 times over 14 days (PMA group). A second group received the same PMA treatment but was not studied until 14 days after the last treatment (PMA/recovery group). A third group was treated with vehicle alone. At the end of PMA treatment, rabbits had an elevated pulmonary artery pressure and depressed ACE activity, expressed as the ratio Vmax/Km. Decreased Vmax/Km for ACE was due to a significant reduction in apparent Vmax for BPAP (control = 235 +/- 37, PMA = 139 +/- 12 nmol/s). Km was unchanged (control = 25 +/- 4, PMA = 31 +/- 7 microM). Uptake of 5-HT was unaffected by PMA treatment. After 2 wk of recovery (PMA/recovery group), pulmonary hypertension had resolved. In this group, Vmax for BPAP hydrolysis was not significantly different from control (280 +/- 18 nmol/s), but Km was significantly increased (48 +/- 5 microM). We conclude that repeated exposure of rabbits to PMA results in lung injury manifested as depressed pulmonary ACE activity and pulmonary artery hypertension. Although much of these alterations were reversible within 2 wk after discontinuing PMA, an increase in apparent Km of ACE may be a more persistent alteration in vascular endothelial cell dysfunction.
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PMID:Resolution of impaired pulmonary function and pulmonary hypertension after phorbol ester administration in rabbits. 255 Dec 5

The effects of a 6 h infusion of 50 ng/kg.min angiotensin I on hemodynamic parameters were recorded in conscious male beagle dogs. Mean arterial pressure was elevated from 107 +/- 3 mmHg to 152 +/- 5 mmHg (mean +/- SEM, n = 5) within the first hour, followed by a slow decrease to 145 +/- 5 mmHg after 6 h. Cardiac output fell from 2.3 +/- 0.2 l/min to 1.6 +/- 0.2 l/min followed by an increase to 2.5 +/- 0.3 l/min. The peripheral resistance showed an exceeding increase from 2.9 +/- 0.2 mmHg.s/ml to 5.7 +/- 0.7 mmHg.s/ml and a slow decrease to 3.5 +/- 0.5 mmHg.s/ml. Heart rate was found to be decreased from 62 +/- 7 min-1 to 58 +/- 7 min-1 after 1 h. The angiotensin converting enzyme (ACE)-inhibitor enalapril caused a complete reduction of the angiotensin induced hypertension. Three new non-sulfhydryl containing ACE-inhibitors ((S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [1-pyrrolidinyl]-glycine (REV 6207), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [2-ethoxyethoxy]-glycine (REV 6134), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylporpyl]-L-alanyl]-N- [phenylmethyl]-glycine (REV 5975] were found to show a partial reduction of the angiotensin I effect. The duration of action which was found to be similar after oral and intravenous administration ranged from 83 +/- 33 min (n = 3) for REV 5975 to more than 360 min for enalapril. A correlation of the arterial pressure lowering and the percentage of the ACE-inhibition suggests that a considerable blood pressure effect can only be observed when more than about 80% of the ACE-activity is inhibited.
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PMID:Hemodynamic effects of new angiotensin converting enzyme inhibitors during continuous angiotensin I infusion on conscious dogs. 284 51

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
Hypertension 1988 Jun
PMID:A highly potent and long-acting oral inhibitor of human renin. 313 6

The antihypertensive effects of altiopril calcium (MC-838), calcium(-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methyl- propionyl]-L-prolinate, a novel inhibitor of angiotensin converting enzyme, compared with captopril, were evaluated in conscious rat models of experimental hypertension. MC-838 (3-30 mg/kg p.o.) as well as captopril (3 and 10 mg/kg p.o.) dose-dependently lowered systemic blood pressure (SBP) with no consistent changes in heart rate (HR) in two-kidney renal hypertensive rats (2 KG-RHRs) and spontaneously hypertensive rats (SHRs). However, MC-838 and captopril, unlike hydralazine, did not significantly produce hypotension in DOCA-salt hypertensive rats. The antihypertensive effect of MC-838, compared with captopril, was characterized by a slower onset and longer duration. When compared on a weight basis of 3 mg/kg, the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action was approximately 2 times longer than that of captopril. MC-838, like captopril, attenuated angiotensin-I (A-I)-induced pressor response, and augmented bradykinin (BK)-induced depressor one in SHRs. However, no correlation was observed between the modification of the SBP response to exogenous i.v. A-I or BK, and the SBP lowering caused by MC-838 or captopril given orally. In contrast, there was a close correlation between inhibition of lung angiotensin converting enzyme (ACE) (but not plasma ACE) and SBP reduction induced by the 2 ACE inhibitors in SHRs. When administered orally once a day for 9 weeks in 2 KG-RHRs and SHRs, MC-838 dose-dependently reduced SBP throughout the treatment period. After withdrawal of treatment with MC-838 there was no rebound increase in SBP. These studies indicate that MC-838 is a promising antihypertensive agent.
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PMID:Antihypertensive action of a novel orally active angiotensin converting enzyme inhibitor altiopril calcium (MC-838) in several hypertensive models of rats: comparison with captopril. 329 42

It has been demonstrated in experiments on non-anesthetized rabbits that conjunctival injection of carnosine (beta-alanyl 1-histidine) caused a decrease in normal intraocular pressure and reduced prostaglandin-induced ocular hypertension. The rapid onset of the pressure response and the absence of papillary dilation in rabbits treated with carnosine were observed. It is concluded that L-carnosine can be used as a potent drug for the prevention of reactive hypertension syndrome.
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PMID:[Effect of carnosine on intraocular pressure]. 335 28

The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.
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PMID:Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498). 609 68

SCH 31846, 1-(N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl)-cis, syn-octahydro-(H-indole-2-S)-carboxylic acid; CI-907; PD 109, 763-2, is a new non-sulfhydryl-containing, angiotensin-converting enzyme (ACE) inhibitor. The present investigation describes its ACE inhibitory properties and compares them to those of MK 421. The diacid of SCH 31846 inhibited rabbit pulmonary ACE with an IC50 of 2.2 nM (MK 421 diacid 2.5 nM). The drug behaved as a competitive and specific inhibitor in vitro. SCH 31846 and its diacid effectively inhibited pressor actions of intravenous injection of angiotensin I (AI) in anesthetized rats. ID50 values were 27 and 11 micrograms/kg for SCH 31846 and SCH 31846 diacid, respectively (MK 421 and MK 421 diacid 57 and 15 micrograms/kg, respectively). Oral administration of SCH 31846 (0.03-1 mg/kg) inhibited pressor actions of AI in conscious rats with a duration of over 16 h at 0.3 and 1 mg/kg. SCH 31846 was 2.2 times as potent as MK 421 in this regard. The diacid of SCH 31846 was considerably less potent than the ester, implying poor oral absorption of the former. Effective ACE inhibition, as judged by attenuation of pressor actions of AI, was noted in dogs after both intravenous and oral administrations of SCH 31846. Onset of action was more rapid than that of MK 421. Intravenous administration of SCH 31846 inhibited the renal vascular actions of intrarenal injection of AI, indicating effective blockade of the renal enzyme. Intracerebroventricular administration of SCH 31846 diacid blocked pressor responses to intracerebroventricular AI, whereas oral administration of SCH 31846 (10 mg/kg) did not, implying that SCH 31846 inhibits brain ACE but does not gain access to the cerebral enzyme when administered orally. These data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor. As such, it should be useful in the treatment of hypertension and heart failure.
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PMID:Angiotensin-converting enzyme inhibitory activity of SCH 31846, a new non-sulfhydryl inhibitor. 619 64


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